PB2150: CARDIAC AMYLOID REACHING FOR EXTENDED SURVIVAL (CARES) TRIALS: 2 PLACEBO-CONTROLLED, DOUBLE-BLIND, RANDOMIZED, PHASE 3 TRIALS ASSESSING CAEL-101 IN PATIENTS WITH MAYO STAGES IIIA/IIIB AL AMYLOIDOSIS
Authors: Ashutosh Wechalekar, Giovanni Palladini, Maria Angelica Molina, Efstathios Kastritis, Juliana Ianus, Julia Catini, C Cristina Quarta, Michaela Liedtke
Journal: HemaSphere (2023)

Topic: 14. Myeloma and other monoclonal gammopathies - Clinical Background: Light-chain (AL) amyloidosis is a rare, progressive, systemic disorder caused by plasma cell dyscrasia (PCD). Amyloid fibrils deposit in organs leading to progressive organ damage and death. Prognosis is poor for patients with cardiac involvement. Median survival is 24 and 4 months for patients in Mayo Stages IIIa and IIIb (based on the 2013 European Modification of the Mayo 2004 staging criteria), respectively. The standard of care (SoC) is anti-PCD therapy to suppress amyloid fibril generation. As yet, there are no therapies that remove deposited fibrils. CAEL-101 is a monoclonal antibody that binds to amyloid fibrils and may facilitate their systemic removal, improve organ function, and increase patient survival. The ongoing trials will evaluate the efficacy and safety of CAEL-101 as a first-in-class treatment to reduce amyloid burden in patients with cardiac AL amyloidosis. Notably, NCT04504825 (Mayo Stage IIIb) is the first randomized, placebo-controlled efficacy clinical trial to formally assess the effects of a pharmacologic agent in this severely ill population. Because the median expected survival for patients in Mayo Stage IIIb is far shorter than for patients in Mayo Stage IIIa (NCT04512235), the sample size required for the former is less than for the latter Aims: The objective of these trials is to evaluate the efficacy and safety of CAEL-101 when administered concurrently with SoC anti-PCD therapy in treatment-naïve patients with cardiac AL amyloidosis in Mayo Stages IIIb or IIIa Methods: These international, multicenter, double-blind, randomized, phase 3 trials, initiated in 2020, are enrolling patients at >100 sites in >20 countries. Newly diagnosed adults with AL amyloidosis Stage IIIb or IIIa measurable hematologic disease, and histopathological diagnosis of amyloidosis with cardiac involvement are eligible. Patients with other forms of amyloidosis, symptomatic orthostatic hypotension, or supine systolic blood pressure <90 mm Hg are ineligible. Patients in Mayo Stages IIIb (N=124; NCT04504825) and IIIa (N=267; NCT04512235) are being randomized 2:1 to receive once-weekly intravenous infusions of CAEL-101 (1000 mg/m2) or placebo for 4 weeks, followed by maintenance dosing every 2 weeks (Figure). In these event-driven studies, treatment will continue to a minimum of 101 and 79 events for 301 and 302, respectively. Patients will receive concurrent institutional SoC anti-PCD therapy at the discretion of the investigator. Overall survival (primary endpoint) will be analyzed via time-to-event log-rank statistics. Secondary endpoints include functional outcomes, quality of life, and echocardiography Results: Summary/Conclusion:Keywords: AL amyloidosis, Treatment, Antibody